1. Field of the Invention
The field of the present invention relates to systems and methods for treating neurologic or psychiatric disorders or conditions relating to the central and peripheral nervous systems, and more specifically, to techniques and delivery apparatus for therapeutic stimulation of neurons.
2. Background
The human brain is a complex organ, with a high incidence of illness. For example, it is estimated that in the United States, about 46% of the population will suffer from a diagnosable psychiatric disorder during their lifetime. Estimated lifetime prevalence by illness categories is: 29% anxiety disorders, 21% mood disorders, 15% substance disorders, 15% personality disorders, 8% attention deficit hyperactivity disorders, 3% psychotic disorders, and 3% autism spectrum disorders.
Neurologic disorders are also highly prevalent in the population. For example, tinnitus (a condition in which the affected person perceives sound in the absence of an external sound source) afflicts about 10% of the population, with a significant percentage of those affected being so severely impaired as to be unable to work or socialize. Chronic pain is reported by a third of the population and one in seven people suffer daily. Chronic lower back pain, which accounts for a significant percentage of all physician office visits in the United States and hundreds of billions of dollars in annual treatment costs, is now also thought to have its origins in the brain.
Fortunately for the many people suffering from neuropsychiatric disorders, treatments are being developed that show a great deal of promise in treating such illnesses. Unfortunately, current treatments prescribed to patients suffering from nervous system disorders are merely palliative, at best, relieving pain but not the underlying cause of the ailment. For example, treatments for neurologic disorders, such as stroke, epilepsy and dementia, are often ineffective and do not address the root cause of the illness.
A. Chemical Treatments
Treatments offered for people suffering from neuropsychiatric disorders generally fall into one of two categories: chemical (psychopharmacologic) or neuromodulation (brain or peripheral nerve stimulation). The majority of psychiatric and neurologic illnesses are treated chemically, i.e., with pharmacologic agents. Neuropharmacologic and psychopharmacologic agents act at synaptic receptors to alter certain brain inputs in ways that reduce symptoms of mental and neurologic illness. However, chemical intervention has significant drawbacks. Often, the medication(s) must be taken for the rest of a patient's life to keep potentially disabling symptoms under control. If the medication regimen is stopped, the symptoms usually return, sometimes to a greater degree than were initially present, because the underlying pathologic neural wiring is not significantly altered. There are also potentially serious side effects, compliance problems, and widespread lack of efficacy (one-third of depressed and schizophrenic patients do not respond to known pharmacologic treatments) associated with medications.
B. Neuromodulation Treatments
In contrast to chemical treatments, neuromodulation involves modulation of the nervous system by electrically activating neurons in the body through stimulation. Neuromodulation treatments may also be neuroplastic. Neuroplasticity is the ability of the brain to rewire itself permanently in response to changing external or internal stimuli. The brain has a high degree of neuroplasticity in childhood, enabling children to learn in a highly efficient manner and heal from potentially devastating neural injuries. However, enhancement of neuroplastic properties for a particular brain area requires specific endogenous or artificial activation methods. Additionally, brain neuroplasticity tends to diminish rapidly with age. As such, age-related neuroplastic constraints can limit the effectiveness of most medical therapy of psychiatric or neurologic illnesses—at least for adults—to a slow, transient, or partial response.
Although still relatively undeveloped, neuromodulation techniques have shown promise in treating nervous system illnesses, including those that are refractory to chemical treatment methods. Neuromodulation techniques generally fall into one of two categories: peripheral nerve stimulation and central nerve stimulation. Central and peripheral neurons function similarly, using voltage-gated ion channels to transmit electrical impulses in the form of action potentials along nerve tracts leading directly or indirectly to specific regions in the brain or spinal cord. However, the two types of neurons differ in their locations; central neurons have cell bodies inside the dura mater enclosing the brain or spinal cord, while peripheral neurons have cell bodies outside the dura mater.
(1) Examples of Peripheral Neuromodulation
Peripheral nerve stimulation activates neurons having cell bodies outside the brain and spinal cord. An example of an invasive (penetrating the skin) peripheral nerve stimulation technique is vagus nerve stimulation (“VNS”). The vagus nerve is a peripheral cranial nerve important for homeostatic physiologic regulation (e.g., decreases heart rate, activates digestive tract), and generally extends from the brainstem to the abdomen, via various organs. VNS typically consists of surgically implanting an electronic stimulation device into the thoracic cavity and attaching linked electrodes. Stimulation of the vagus nerve transmits electrical impulses upward through the chest, neck, and skull base into the brainstem.
Another cranial nerve stimulation technique that is non-invasive is known as trigeminal nerve stimulation (“TNS”), which stimulates the superior branch of the trigeminal nerve. The axons of this nerve travel from the skin in the upper scalp, forehead and cranium to their extradural cell bodies inside the skull located the trigeminal nerve ganglion. Here, these neurons have synapses connecting them to various brain regions inside the dura mater. This is a relatively new and exciting technique, the effects of which are only now beginning to be explored.
(2) Example of Central Neuromodulation
In contrast to peripheral nerve stimulation, brain stimulation directly stimulates the brain or spinal cord. Transcranial magnetic stimulation (“TMS”) is an example of brain stimulation. TMS is a non-invasive technique that typically involves placing an electromagnetic coil on or near the patient's head to depolarize or hyperpolarize neurons in specific brain areas. In particular, TMS uses electromagnetic induction to induce weak electrical currents using a rapidly changing magnetic field to increase or decrease activity in one or more brain regions.
TMS has diagnostic uses including determining the contribution of cortical networks to specific cognitive functions by disrupting activity in the focal brain region. TMS also has a number of therapeutic uses. For example, a variant of single pulse TMS is repetitive transcranial magnetic stimulation (“rTMS”). Repetitive TMS has been tested as a treatment tool for various neurological and psychiatric disorders including migraines, strokes, Parkinson's disease, dystonia, tinnitus, depression, and auditory hallucinations. The term repetitive transcranial magnetic stimulation is often used interchangeably with the term transcranial magnetic stimulation in the clinical domain. Likewise, the abbreviation rTMS is sometimes used interchangeably with TMS. For convenience, the term transcranial magnetic stimulation and abbreviation TMS will be used herein to encompass both single pulse and repetitive transcranial magnetic stimulation.
TMS techniques typically act on a volume of brain tissue that is approximately two to three centimeters in diameter. The localized nature of the intervention avoids systemic side effects that commonly plague current pharmacologic treatments. This type of approach also avoids adverse medication interactions and the difficulty of ascertaining compliance with treatment as the patient must be physically present for treatment to occur.
As with most any medical treatments, currently known TMS techniques also entail potential side effects or risks, including headache or local scalp discomfort, hypomania in bipolar patients, and in rare cases seizure activity. A patient's hearing may also be adversely affected, although there are not any reports of this occurring in humans. During treatment, rapid deformation of the TMS coil produces a loud clicking sound that increases with the stimulator intensity. Such clicking can theoretically affect hearing with sufficient exposure. Consequently, hearing protection is typically used during TMS treatment.
Recent advances have been made to neuromodulation treatments. For example, a novel therapeutic system comprising a brain stimulation device configured to stimulate a patient's brain by emitting an electromagnetic field based on certain stimulation parameters, a feedback device configured to measure data regarding brain activity, and a computer communicably connected to the feedback and stimulation devices has been.
While a substantial amount of research has shown that neuromodulation is safe and effective, questions remain about long-term efficacy and robustness. For example, current TMS techniques have not proven to be effective on all patients. In addition, significant relapse rates exist, requiring that the affected patient seek additional treatment possibly including additional TMS sessions.
(3) Comparison of Neuromodulation Techniques
Table 1 below compares some known electromagnetic neuromodulation techniques and illustrates certain characteristics of each. Only the last technique uses focused ultrasound to stimulate neurons; the remainder act electromagnetically. The laws of physics dictate that all electromagnetic fields have an electrical and a magnetic component, but neuromodulatory electromagnetic fields may act principally through their electrical component, their magnetic component, or a combination. Although neuromodulation techniques use different mechanisms of action, the end results are the same; hyperpolarization or depolarization of neural cell membranes is the final common pathway leading to therapeutic change. Similar pulse parameter sets applied using different neuromodulation techniques will likely have very similar effects due to the fact that neuromodulation is, by definition, a change in neural firing rates determined by the membrane potential of the associated target neurons. Therefore effective pulse parameter sets will likely have a universal value among the many forms of neuromodulation.
TABLE 1Comparison of Neuromodulation TechniquesNon-ExternalHome or Of-BrainStimulation TypeAbbrevMagneticInvasiveDevicefice ProcedureStimulationTranscutaneousTENSNOYESYESYESNOElectrical NerveStimulationTranscutaneoust-VNSNOYESYESYESNOVagal NerveStimulationTrigeminal NerveTNSNOYESYESYESNOStimulationPeripheral NervePNFSNONONOYESNOField StimulationPeripheral NervePNSNONONONONOStimulationVagus NerveVNSNONONONONOStimulationTranscranialTESNOYESYESYESYESElectrical Stimulation(Direct Current,tDCSAlternating Current,tACSRandom Noise)tRNSPaired AssociativePASYESYESYESYESYESStimulationTranscranialTMSYESYESYESYESYESMagnetic StimulationDeep TranscranialdTMSYESYESYESYESYESMagnetic StimulationMulti-CoilmTMSYESYESYESYESYESTranscranialMagnetic StimulationDeep BrainDBSNONONONOYESStimulationMagnetic SeizureMSTYESYESYESNOYESTherapyElectroconvulsiveECTNOYESYESNOYESTherapyFocused UltrasoundFUSNOYESYESYESYES
(4) TMS Delivery Techniques
Different techniques have been explored for delivering pulses in connection with TMS treatments. One particular TMS variant, known as Theta Burst Stimulation (TBS), involves the application of short bursts of relatively high-frequency (e.g., 50 Hz) pulses that may be applied continuously, or else repeated at a theta frequency (generally in the range of 4-8 Hz), upon the target site. Animal studies have long established that TBS can be an effective and safe method to induce changes in cortical excitability. Until relatively recently, it has only been applied to animals. However, in 2005, researchers reported safe and tolerable application of TBS in humans. See Huang, Y. Z., et al., Theta Burst Stimulation of the Human Motor Cortex, Neuron, 45(2), pp. 201206 (2005). In that study, TBS was applied as short bursts with three pulses/burst occurring at a pulse frequency of 50 Hz (i.e., separated by 20 millisecond intervals). These bursts were repeated at a burst frequency of 5 Hz (i.e., every 200 milliseconds). The TBS paradigm reported by Huang et al. was widely adopted by fellow researchers, who noted that TBS appeared to be superior to tonic stimulation in terms of inducing cortical excitability. There are other types of burst stimulation which may occur with burst frequencies in the delta range (0-4 Hz), alpha range (8-12 Hz), beta range (12-30 Hz) or gamma range (30-100 Hz), as generally described for example in De Ridder, D., et al., Theta, Alpha And Beta Burst Transcranial Magnetic Stimulation: Brain Modulation In Tinnitus, International Journal Of Medical Sciences, 4(5), 237 (2007).
Two kinds of theta burst stimulation have clinical relevance. The first type is referred to as “continuous” TBS (cTBS) and generally involves a continuous train of bursts applied to the target site, while the second type is referred to as “intermittent” TBS (iTBS) and generally involves a short train of bursts (typically 10 bursts) separated by an intertrain interval (typically several times longer than the duration of the train). iTBS and cTBS modulate human cortical excitability differently, with iTBS generally increasing it and cTBS generally decreasing it, according to past studies. When applied to motor cortex, TBS can cause long-term changes in motor-evoked potentials, with iTBS typically increasing the amplitude and cTBS typically decreasing the amplitude.
Several studies of human motor-evoked potential have indicated that TBS yields longer lasting post-stimulation effects on cortical activity than conventional TMS. These post-stimulation effects which outlast the stimulation interval are frequently referred to as long-term potentiation and long-term depression. Researchers have also found that long-term potentiation and long-term depression are not limited to motor cortex but occur in multiple brain regions. In addition, a few studies have noted that large pulse sequences of 1200 or more pulses divided into four sets of 300 pulses each delivered at increments of 15 minutes may increase the duration of the effect on motor-evoked potential.
(5) TBS Studies in Humans
TBS treatment has been considered for treatment of psychological disorders. Currently, however, there are only a handful of reported studies involving TBS for the treatment of depression. The most exhaustive of the three is an Israeli study assessing the effectiveness of a two-week TBS treatment using a burst frequency of 5 Hz and a pulse frequency of 50 Hz (TBS-50 Hz) on 32 patients diagnosed with depression. The results of this study were published in Chistyakov et al., Safety, Tolerability And Preliminary Evidence For Antidepressant Efficacy Of Theta-Burst Transcranial Magnetic Stimulation In Patients With Major Depression, International Journal of Neuropsychopharmacology, Vol. 13, No. 3, pp. 387-393 (2010). In this study, the patients were divided into two groups to assess laterality of treatment, as well as overall efficacy of theta 50 treatment. The first group received iTBS treatment applied as a 2 second train repeated every 10 seconds to the left dorsolateral prefrontal cortex (LDLPFC). The second group received cTBS applied as a single uninterrupted train to the right dorsolateral prefrontal cortex (RDLPFC). The patients were further divided into three sub-groups to evaluate dosage effect. The first group received 1200 stimuli per day, the second group received 1800 stimuli per day and the third group received 3600 stimuli per day. The results of this study showed an overall response rate (measured as 50% reduction of Hamilton Depression Rating Scale (HDRS) scores) of 56.3%. The results also indicated a dose effect since the increase of the number of stimuli added to the therapeutic effect.
The second study, conducted in Germany, also evaluated the therapeutic effect of TBS upon patients with depression, but limited the study to unilateral stimulation of the left dorsolateral prefrontal cortex (LDLPFC). The results of this study were published in Holzer et al, Intermittent Theta Burst Stimulation (iTBS) Ameliorates Therapy-Resistant Depression: A Case Series, Neuromodulation Vol. 3, Issue 3, pp. 181-183 (2010). In this study, seven treatment refractory patients received two daily sessions of TBS-50 Hz stimulation at 80% of resting motor threshold (rMT) over a three-week treatment period. Each iTBS sequence contained 600 pulses applied in an intermittent theta burst pattern with a 2 second stimulation interval and an 8 second intertrain interval. After the three weeks of treatment, Hamilton Depression Rating Scale (HDRS) scores dropped by 43% and Beck Depression Inventory (BDI) scores dropped by 49%. Three patients (42% remission rate) achieved remission and five patients (70% response rate) met the criteria for response.
A third study was reported in Wu et al, Continuous Theta Burst Stimulation Of Right Dorsolateral Prefrontal Cortex Induces Changes In Impulsivity Level, Brain Stimulation Vol. 3, Issue 3, pp. 170-176 (2010). In that study, researchers reported improvement in a patient with treatment-resistant obsessive-compulsive disorder and major depressive disorder. The treatment involved TBS-50 Hz applied sequentially to bilateral cortical targets, with 10 sessions of cTBS over patient's right dorsolateral prefrontal cortex (RDLPFC) followed by 10 sessions of two seconds stimulation, 8 second intertrain interval iTBS over his left dorsolateral prefrontal cortex (LDLPFC). After six weeks of this treatment, a significant reduction of the patient's symptoms was noted, including a 34 point drop (from 49 to 15) of his Hamilton Depression Rating Scale (HDRS) score.
Although the results of the above studies are of interest, the TBS protocols employed did not, or are not proven, to work universally on all patients. Further, the level of benefit varied from patient to patient. In other studies or clinical experience, performed by or under the direction of the inventor of the disclosed invention herein, some patients receiving a TBS treatment with a 50 Hz repetition rate did not experience a decrease in their depression symptoms. The results from the earlier studies are also unproven in terms of duration of relief, relapse rate, and overall safety and efficacy, including long-term effects, which have not been well studied.
TBS is more comfortable for patients because, contrary to tonic stimulation, it is generally administered at an intensity below motor threshold. TBS also can be advantageous over tonic stimulation because the pulses are more concentrated which shortens treatment times. For example, a patient whose treatment regimen is 3600 pulses over RDLPFC using tonic 1 Hz inhibitory stimulation requires an hour of treatment time. The same protocol using cTBS only requires a treatment period of four minutes. However, excitatory TBS may require a treatment period in the range of 15-20 minutes or more.
In sum, current neurologic and psychiatric treatments leave considerable room for improvement. It would therefore be advantageous to provide novel and effective systems and methods of treating neurologic or psychiatric disorders that are non-chemical, non-invasive, neuroplastic, and curative.
It would further be advantageous to provide more efficacious systems and methods for delivering therapeutic neuromodulatory stimulation to the brain. It would also be advantageous to provide systems and methods for neuromodulatory stimulation to the brain that yield results in a greater percentage of the population, that provide a greater reduction in adverse symptoms, provide longer lasting effects, and/or reduce the rate of relapse. It would also be advantageous to provide systems and methods for neuromodulatory stimulation to the brain that require less time to administer, without substantially sacrificing, or while improving, actual or potential efficacy.
In addition to the above, or alternatively, it would be advantageous to provide systems and methods for neuromodulatory stimulation to the brain that are safer to the patient, require shorter treatment times, and improve patient comfort during therapy, without substantially sacrificing, or while improving, actual or potential efficacy.
It would further be advantageous to provide systems and methods for conveniently determining and/or selecting parameters for neuromodulatory techniques. Likewise, it would be advantageous to provide systems and methods for electromagnetic stimulation to the brain that require less specialized knowledge or training, and are able to be administered by a wider population of medical or other personnel.